Nodal, a potent embryonic morphogen in the transforming growth factor-beta family, is a proposed key regulator of melanoma tumorigenicity. However, there has been no systematic study of Nodal expression in melanocytic lesions. We investigated Nodal expression by immunohistochemistry in 269 melanocytic lesions, including compound nevi, dysplastic nevi, congenital nevi, Spitz nevi, melanoma in situ, malignant melanoma including the variant desmoplastic melanoma, and metastatic melanoma. We found that the Nodal expression was significantly increased in malignant lesions (including melanoma in situ, malignant melanoma, and metastatic melanoma) compared with compound nevi, Spitz nevi, and dysplastic nevi. Surprisingly, congenital nevi expressed a level of Nodal comparable with malignant lesions, whereas desmoplastic melanoma showed lower expression than nondesmoplastic malignant melanoma (P<0.05). Deep melanoma (Breslow depth >1 mm) displayed a higher percentage of Nodal-positive tumor cells than did superficial melanoma (Breslow depth < or =1 mm), although there was no statistical difference in the overall staining intensity (P=0.18). Melanomas in situ showed a lower level of Nodal expression than did deep melanomas and metastatic melanomas (P<0.05). The low expression of Nodal in normal and dysplastic nevi, and its increasing expression with the progression of malignant lesions, are suggestive of a role for Nodal in melanoma progression.